Platelet-derived growth factor C (PDGF-C), is, in humans, a 345-amino acid protein which is secreted as a 323-amino acid protein (Hamada et al. 2000, FEBS Lett 475:97-102; Li & Eriksson 2003, Cytokine Growth Factor Rev 14, 91-98). It is a member of the platelet-derived growth factor family which consists of PDGF-A, -B, -C and -D (Li et al. 2000, Nat Cell Biol 2:302-309; Bergsten et al. 2001, Nat Cell Biol 3:512-516; La Rochelle et al. 2001, Nat Cell Biol, 3:517-521). The cysteine knot motif characteristic of the four PDGFs is key to the formation of either homo- or heterodimers (PDGF-AA, -AB, -BB, -CC, -DD) (La Rochelle et al. 2001, Nat Cell Biol 3:517-521; Bergsten et al. 2001, Nat Cell Biol 3:512-516).
In addition to a conserved cystine knot motif, these four growth factors show sequence homology. The four PDGFs are inactive in their monomeric forms. In case of PDGF-C, it is secreted as latent growth factor and proteolytic removal of the N-terminal CUB domain is required for binding to and activation of its receptor. While there are some reports that CUB domains are biologically active, the prevailing thought is that they function to both localize the secreted PDGF-C and repress its activity (Reigstad et al. 2005, FEBS J 272:5723-5741). Proteases capable of activating PDGF-C include plasmin and tissue plasminogen activator (tPA) (Lei et al. 2007, Invest Ophthalmol Vis Sci 48:2335-2342; Lei 2008, Invest Ophthalmol Vis Sci 49:42-48.)
PDGF-C regulates biological processes via homodimeric PDGF receptor alpha (PDGFRα), and possibly via heterodimeric PDGFRα/β. The extracellular region of the receptor consists of five immunoglobulin-like domains while the intracellular part is a tyrosine kinase domain. PDGF-CC binding to its receptor boosts the activity of the tyrosine kinase domain and thereby initiates intracellular signalling events that trigger cellular responses such as proliferation, migration, contraction and survival (Li et al. 2000, Nat Cell Biol 2:302-309). Thus PDGF-C activates intracellular signalling events that engage a host of cellular responses that are essential for numerous biological processes that are required for the development and health of mammals. Mouse knockout studies show that PDGF-C is required for palatogenesis (Fredriksson et al. 2004, Cytokine Growth Factors Rev 15:197-204; Reigstad et al. 2005, J Biol Chem 278:17114-17120). Abnormalities in the PDGF/PDGFR system such as constitutive activation of PDGFR kinases, activating mutations of the PDGFR kinases, autocrine signalling due to overexpression of PDGFs and the PDGFRs, contribute to a number of human diseases, especially malignancies including osteosarcomas, lung carcinomas, gliomas, and malignant astrocytomasand medulloblastomas (Locker et al 2002, Cancer Res 62:3729-3735; Ekman et al. 1999, Oncogene 18:2481-2488; Zwerner & May 2002, Oncogene 21:3847-3854). PDGF-C is a transforming cell factor and promotes tumor growth via several mechanisms including survival and proliferation of tumor cells, chemotaxis for cancer-associated fibroblasts, and tumor neovascularization. It has been demonstrated that PDGF-C induces tumors in nude mice, activates anchorage dependent growth, and is a potent transforming growth factor of NIH/3T3 cells. (Li et al. 2002, Oncogene 22:1501-1510). The in vivo tumourigenesis may partially be explained by PDGFC-mediated VEGF expression, promoting indirect stimulation of tumor angiogenesis. Finally, PDGF-C is upregulated in cancer tumors that are resistant to chemotherapy. In preclinical models of cancer, siRNA-mediated reduction of PDGF-C levels reverses the resistance to cisplatin (Yamano et al. 2010, Int J Cancer 126:437-449).
PDGF-C used to be termed VEGF-E (WO99/47677) or ZVEGF3 (WO00/34474). Although the use of antibodies countering PDGF-C activity (or of bispecific anti-VEGF/anti-PDGF-C antibodies) has been suggested (WO99/47677, WO00/34474, WO01/28586, WO2005/011742, WO00/18212, WO 2005/087812), not any specific monoclonal antibody with demonstrated anti-tumorigenic or anti-angiogenic activity has as yet been reported.